Cannabidiol improves L-DOPA-induced dyskinesia and modulates neuroinflammation and the endocannabinoid, endovanilloid...

Despite the widespread use of L-3,4-dihydroxyphenylalanine (L-DOPA) as the gold standard for dopamine (DA) replacement in Parkinson's Disease (PD), its prolonged administration frequently leads to L-DOPA-induced dyskinesia (LID), a significant therapeutic challenge. Modulating the endocannabinoid system has emerged as a promising approach for managing LID. This study explored whether cannabidiol (CBD), a non-psychoactive compound of Cannabis sativa, and PECS-101, a fluorinated derivative of CBD, could mitigate the onset and progression of LID. We used unilateral 6-hydroxydopamine-lesioned rats, treated with L-DOPA (10 mg kg - 1) for three weeks to induce severe abnormal involuntary movements (AIMs). Treatments were administered during the final two weeks. CBD (30 mg kg - 1) and PECS-101 (3 and 30 mg kg - 1) significantly reduced AIMs without impairing the motor benefits of L-DOPA. The antidyskinetic effects of CBD were associated with decreased striatal Fos-B and phospho-ERK expression and were independent of lesion severity. CBD effects were prevented by antagonists of CB1 (1 mg kg - 1) and PPARγ (4 mg kg - 1) receptors. Co-administration of TRPV-1 antagonist capsazepine (5 mg kg - 1) enhanced the antidyskinetic effects of CBD. Combining the capsazepine with the neuronal nitric oxide synthase inhibitor, 7-nitroimidazole (10 mg kg - 1) enhanced these effects. CBD did not alter striatal DA levels but significantly increased the concentrations of anandamide and 2-arachidonoylglycerol in dyskinetic animals. The antidyskinetic effects of CBD were associated with a reduction of the enhanced striatal glia and peripheral inflammation markers. These findings suggest that CBD alleviates LID by interacting with the nitrergic neurotransmission and TRPV-1, CB1, and PPARγ receptors.